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DOI: 10.1542/neo.11-7-e3432010;11;e343Neoreviews
Roland R. Wauer and Charles Christoph Roehrand CPAP in Extremely Low Gestational Age Neonates, Vienna 2009
International Perspectives : Report on the International Seminar on Surfactant
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Drs Wauer and Roehr have disclosed
no financial relationships relevant to
this article. This commentary does
not contain a discussion of an
unapproved/investigative use of a
commercial product/device.
Report on the International Seminaron Surfactant and CPAP in ExtremelyLow Gestational Age Neonates,
Vienna 2009Roland R. Wauer, MD, PhD*, Charles
Christoph Roehr, MD* for the Scientific
Committee
The following article in our Interna-
tional Perspectives series differs some-what from the usual format. Most of
these pieces either cover what is hap-
pening in a particular country or pro-
vide a regional viewpoint on a selected
topic. The report of this seminar was
suggested by one of our International
Advisory Board members (Dr Mats
Blennow from Stockholm, Sweden)
and provides some insight into what is
currently considered to be important
by influential neonatologists in Eu-
rope. It also provides direction forfuture research activity in several dif-
ferent areas, which may stimulate
some of our North American readers
(as well as our European colleagues).
Not all references provided by the
speakers are included with this report.
The complete list of references may be
obtained by contacting Dr Roehr at
[email protected]. Publication
of this report should not be seen as an
open invitation to submit the pro-
ceedings of all such meetings toNeoReviews. However, there might be
a place for other reports of interna-
tional seminars/symposia, if they deal
with topics that are considered to be of
general interest and have not been cov-
ered in recent issues of the journal.
Alistair G.S. Philip, MD
Editor-in-Chief,NeoReviews
BackgroundThis seminar originated as a spon-
sored research seminar, initiated by
the European Respiratory Society
(ERS) and the Charite Universitas-
medizin Berlin, Germany. At the in-
vitation of the organizing committee(C. Roehr/R. Wauer/A.Greenough/
H. Verder), an international panel
of expert neonatologists and re-
searchers in neonatal medicine pre-
sented the latest data on managing
extremely low gestational age neo-
nates (ELGANs) with continuous
positive airway pressure (CPAP) and
surfactant. The presentations fo-
cused on the pathophysiology of
neonatal lung disease and the pre-
vention and treatment of respiratory
distress in ELGANs. The interna-
tional audience comprised respirolo-
gists, physicians, physiologists, and
neonatal practitioners. Aims of the
seminar were to: 1) Discuss the best
available evidence regarding the use
of surfactant and CPAP in ELGANs,
2) Identify and focus on areas of ur-
gently needed research, and 3) form
international collaborations for fu-
ture research. There was a lively and
productive discussion in between the
presentations and during breaks aswell as during the final panel session.
The individual contributions from
the speakers are summarized in this
article, and pertinent references are
included at the end of the summary.
PresentationsAlan Jobe (Cincinnati Childrens
Hospital, Cincinnati, Ohio, United
States) began with a brief History
of CPAP for Preterm Infants With
*Neonatology Clinic, Charite, Berlin University,
Berlin, Germany.
international perspectives
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RDS. After having been pushed
aside by mechanical ventilation (used
with positive end-expiratory pres-
sure [PEEP]) in the mid-1970s and
1980s, the high incidence of bron-
chopulmonary dysplasia (BPD) in
survivors of mechanical ventilation
resulted in a rebirth of CPAP as a
noninvasive technique to try to de-
crease lung injury. CPAP once again
is used frequently as an initial ther-
apy for respiratory distress syndrome
(RDS), with and without surfactant
administration, as early as in the de-livery room. Many new types of
CPAP applications are available, but
the benefits of CPAP in preventing
BPD remain unproven by random-
ized, controlled trials. Dr Jobe con-
cluded that CPAP is being embraced
with a new enthusiasm in 2009.
In his talk Breathing of Preterm
Infants at Birth, Arjan te Pas (Lei-
den, the Netherlands) focused on gas
flow patterns during the first breaths
after birth. He presented new evi-dence that spontaneous breaths dif-
fer completely from those seen when
manual inflations are given during
neonatal resuscitation. At birth, pre-
term infants use intrinsic PEEP and
expiratory breaking, predominantly
characterized by a breath hold, to
create and maintain lung volume. He
hypothesized that the effectiveness
of respiratory support in the delivery
room may be improved by using a
strategy of aeration similar to sponta-neous breathing patterns. During
manual inflation, delivery of PEEP
should be guaranteed and breath
hold could be mimicked by giving
several sustained inflations. It ap-
pears possible that this approach
(CPAP and sustained inflations) may
prove to be superior in supporting the
breathing pattern of a preterm infant
who is breathing insufficiently, rather
than simply taking over and provid-
ing manual inflations (seeTable 1in
data supplement for issues and pro-
posed actions).
Jane Pillow(University of West-
ern Australia, Perth, Australia) stated
in her topic Transitional Changes
During the First Minutes in Life
Outside the Womb: Understanding
the Mechanisms of Lung Injury
that static and cyclic volutrauma and
exposure to toxins (eg, high oxygen
concentrations) remain the central
issues in resuscitation research, estab-
lishing the optimal transition to post-
natal life. In her opinion, other mod-
ifiable environmental factors alsomay influence lung injury. For exam-
ple, heat, humidification, and flow of
the inspired air (so-called condition-
ing of gas or gas conditioning);
body temperature; and distribution
of surfactant all may be involved.
These areas urgently warrant further
research. Focusing on the establish-
ment of functional residual capacity
(FRC) and using examples from re-
cent studies by te Pas and coworkers
with phase contrast imaging of thefirst postnatal breaths in newborn
rabbit pups, she stated that establish-
ment of FRC is primarily dependent
on PEEP. In contrast, establishment
of adequate and appropriately dis-
tributed tidal volumes can be
achieved rapidly with sustained infla-
tions. Supporting the data from
tePas, she also suggested that the
combination of sustained inflations
with the first breaths and the use of
PEEP during resuscitation may helpestablish noninjurious cyclic ventila-
tion at appropriate FRC more effec-
tively and efficiently than alternative
approaches.
During the final discussion, both
te Pas and Pillow stated that further
research studies are in progress that
should help to define further the
optimal application of sustained in-
flations and establish whether the
physiologic benefits translate into re-
duced lung injury. They stressed that
depending on the outcome of these
studies, planning of clinical trials to
assess the merits of these approaches
in human infants would be appropri-
ate in the near future.
Bronchopulmonary Dysplasia:
One Disease or Two? asked Mario
Rudiger(Neonatology, Carl Gustav
Carus Universitat, Dresden, Ger-
many). He stated that classical
BPD and new BPD not only dif-
fer in their clinical pictures but also
in their pathogenesis and morphol-
ogy. The arrest in alveolarization
seen in patients who have new BPDis believed to result from a postnatal
disturbance of lung development.
Alveoli develop in utero at low oxy-
gen concentrations, but ELGANs
are exposed to relative hyperoxia,
even if breathing room air. Relative
hyperoxia leads to a decrease in
hypoxia-inducible factor and its
products, such as vascular endothe-
lial growth factor (VEGF). Rudiger
proposed that future research con-
centrate on clinically useful markersfor better discrimination between the
two types of BPD. In a second step,
interventions should be tailored ac-
cording to the pathogenesis of each
and targeted to either type of disease.
Whereas steroids might be appropri-
ate for classical BPD, the new BPD
may be prevented by substituting
lung growth factors, such as VEGF,
or by reducing the effects of relative
hyperoxia.
Colm ODonnell(Neonatal Ser-vices, National Maternity Hospital,
Holles Street, Dublin, Ireland) spoke
about Handling of the Neonate in
the First Minutes of Life: Practical
Observations. He found that new-
borns often were handled roughly,
dried vigorously, and suctioned per-
haps too enthusiastically. Preterm in-
fants most often cried and breathed
spontaneously after birth, even be-
fore any respiratory support was
given, and clinical assessment of in-
international perspectives
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fant condition at birth was highly
subjective, with observers frequently
disagreeing. He concluded that the
standard approach to all infants at
birth appears to be to suspect that
they will behave like, and respond
to the same treatment, as an acutely
asphyxiated term animal. Such an
approach may lead to term and pre-
term infants receiving interventions
that are not helpful and potentially
harmful.
During the final discussion, the
panel accepted that filming is a useful
tool for reviewing and improving re-suscitation skills. Although seminar
participants agreed that videotaping
seems useful for research and educa-
tional purposes, it is not yet ready for
use in day-to-day clinical practice.
Kajsa Bohlin (Neonatal Depart-
ment, Karolinska Institute, Stock-
holm, Sweden) summarized the
Effect of Different Ventilation
Techniques on Surfactant Stability
and Metabolism. The surfactant
synthesis rate is slow, and the recy-cling of surfactant components be-
tween the airspaces and alveolar type
II cells is more important in preterm
compared with term lungs. The effi-
cacy of exogenous surfactant treat-
ment depends on distribution of sur-
factant, surfactant metabolism, and
lung injury, all of which can be influ-
enced by ventilation strategy. Careful
delivery room management is crucial
because even only a few large breaths
may impair surfactant treatment re-sponse and distribution pattern. Sur-
factant metabolism during CPAP
and promising new lung protective
ventilation strategies require further
study, as does a means to reduce the
susceptibility to inhibition of exoge-
nous surfactant. Methods to assess
the need for surfactant treatment and
studies on how to incorporate sur-
factant administration into an early
CPAP protocol to ensure optimal
treatment response are warranted.
Anne Greenough (Kings Col-
lege Hospital, London, United
Kingdom) gave an overview on Me-
chanical Ventilation Versus CPAP:
What are the Pros and Cons? She
summarized four primary points:
1) Results from randomized trials
suggest prophylactic or early nasal
CPAP may reduce BPD, but further
studies are required to determine
the relative contributions of an early
lung recruitment policy, early sur-
factant administration, and nasal
CPAP in reducing BPD. 2) High-
volume high-frequency oscillatoryventilation (HFOV) reduces BPD,
but whether it improves long-term
lung function requires follow-up of
infants entered into randomized,
controlled trials. 3) Weaning from
the respirator is best achieved by us-
ing modes supporting every breath.
4) A trial of rescue HFOV in severe
respiratory distress with long-term
outcomes is needed.
The topic ofAngela Kribs(Neo-
natology, Universitatsmedizin, Koln,Germany) was Treating Preterm
Infants With Surfactant: An Over-
view of Application Techniques
and Results. After demonstration
of published methods of surfactant
application in the delivery room (in-
trapartum into the nasopharynx be-
fore birth of the shoulders, via a
laryngeal mask, nebulization) and
discussion of the pros and cons, she
presented her preferred method of
surfactant application via a thin en-dotracheal catheter during spontane-
ous breathing in ELGANs. After in-
troduction of this method, the need
for mechanical ventilation was re-
duced from 77% to 48%, mortality
from 35% to 12%, and the incidence
of more than second-degree intra-
ventricular hemorrhage from 32% to
5% compared with historical con-
trols. The new method is being
tested in two prospective, random-
ized trials.
Colin Morley (Melbourne, Aus-
tralia) spoke about Understanding
CPAP: Why Does It Work and When
Should We Use It? He presented
data about how CPAP aids the for-
mation and maintenance of FRC,
improves oxygenation, reduces air-
way resistance, improves compliance,
conserves surfactant, improves the
respiratory pattern, and reduces the
need for ventilation in preterm in-
fants. He suggested that the indica-
tions for the use of CPAP were: all
very preterm infants breathing at
birth, all infants who have dyspnea,and for apnea and postextubation in
preterm infants. He concluded that
more research is needed to under-
stand how CPAP works in different
situations and the optimum pressure
or device and interface to use. It is
also necessary to investigate which
infants do well with nasal CPAP early
on and which ones will fail CPAP and
require early intubation, ventilation,
and surfactant (see Table 2 in data
supplement for issues and proposedactions).
In his topic How is CPAP Cur-
rently Being Used: An Overview,
Charles Christoph Roehr (Berlin,
Germany) reported results from two
questionnaire-based surveys of 274
institutions from German-speaking
countries about the clinical indica-
tions for and type of CPAP equip-
ment used. The primary indications
were treating RDS (98%) and apnea-
bradycardia-syndrome (96%) andfollowing extubation (98%). Com-
mercial CPAP systems (mostly
respirator-generated) were used by
71% of units, with exclusively
mononasal by only 9%, exclusively
binasal by 55%, and all other units
using both interfaces. The reported
differences (in the starting and max-
imum tolerated pressure) reflect per-
sonal experiences and preferences
rather than sound evidence from
clinical trials. Several questions re-
international perspectives
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garding the clinical use of CPAP re-
main unanswered, such as the appro-
priate device and pressure for specific
clinical conditions, the ideal individ-
ual level of flow, and a practical pro-
tocol for weaning from CPAP. Such
questions should be answered in
well-conducted clinical trials.
Speaking on CPAP and PEEP
Provision: Physiologic Effect of Dif-
ferent Pressure Levels, Mathias
Nelle(Berne, Switzerland) reviewed
the literature about effects of nasal
CPAP on different organ systems in
neonates, especially how lung com-pliance, cardiac output, and blood
flow to various organs can be af-
fected. He suggested that many
questions remain unanswered and
the topic remains somewhat con-
troversial. Generally, nasal CPAP
appears to be well tolerated in neo-
nates, but factors influencing circula-
tion should be known and consid-
ered in daily treatment procedures.
Gerd Schmalisch (Berlin, Ger-
many) provided insight into theMonitoring of Ventilation and Air
Leakage During CPAP. In contrast
to adults, little is known about vol-
ume and air leakage monitoring dur-
ing CPAP in neonates because the
measuring conditions are difficult
and suitable equipment currently is
not available. Mostly, indirect meth-
ods (transthoracic impedance mea-
surements, breathing belts) are used.
However, these techniques do not
allow reliable volume measurementsand do not give any information
about air leakage. In a survey, several
different direct measurement tech-
niques to assess ventilation and air
leakage based on the different CPAP
interfaces (facial mask, head box,
mono- or binasal prongs, pharyngeal
or endotracheal tubes) were de-
scribed, and their suitability was
tested in clinical studies. Based on
modeling, the relationship between
air leakage, leak flow, and volume
error were investigated and validated
by in vitro measurements. The cur-
rent display of air leakage as a per-
centage of measured patient ventila-
tion has several disadvantages and
should be replaced by direct mea-
surement and display of leakage flow.
The measurement of the leakage flow
may be helpful in assessment of
CPAP treatment and the prevention
of adverse effects (eg, impairment of
the nasal or upper airway mucosa).
Essence, Reflection, and
OutlookDuring the final panel session of all
experts, the following issues that
might be answered by further re-
search were emphasized: 1) Basic re-
search on CPAP in the delivery room
and evaluation of its chronic use;
2) Cross-over study to find the opti-
mal CPAP level, independent of
FiO2 enhancement; 3) Search for
parameters/methods to describe
better the adaptation process of the
term and preterm infant and theestablishment of FRC; 4) Search
for clinical evidence of the necessity
for gas conditioning in the deliv-
ery room and during transport;
5) Search for the optimal CPAP in-
terface between apparatus and infant
(mask, single tube, binasal prongs,
head box); and 6) Practical parame-
ters for identification of preterm in-
fants who only need CPAP and those
who need additional surfactant (see
Table 3in data supplement for issuesand proposed actions).
The enthusiastic atmosphere of
the seminar, its results, and the fruit-
ful discussions delighted the partici-
pants and encouraged the organizers
and speakers to continue this collab-
oration. Thanks to the generosity of
the ERS, funding for a further re-
search seminar at the upcoming ERS
Congress in Barcelona on September
18, 2010, is planned. The seminar
will concentrate on Managing the
Lung of the Extremely Low Gesta-
tional Age Neonate (ELGAN) in the
Delivery Room.
The seminar was generously
funded by unconditional research
grants by the ERS, Chiesi, Fisher &
Paykel Healthcare, and Abbott Phar-
maceuticals.
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American Board of Pediatrics
Neonatal-Perinatal Medicine
Content Specifications
Know the clinical
strategies andtherapies used to
decrease the risk
and severity of
RDS.
Know the indications for and
techniques of continuous positive
airway pressure (CPAP),
Know the effects and risks of CPAP.
international perspectives
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DOI: 10.1542/neo.11-7-e343
2010;11;e343NeoreviewsRoland R. Wauer and Charles Christoph Roehr
and CPAP in Extremely Low Gestational Age Neonates, Vienna 2009International Perspectives : Report on the International Seminar on Surfactant
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